The overall objective of the proposed research is to discover a PPAR?-sparing thiazolidinedione (TZD) which displays efficacy in a rodent model of non-alcoholic fatty liver disease (NAFLD) and demonstrates the necessary drug-like qualities to become a potential clinical candidate for human therapeutics. The TZD class of insulin sensitizing agents are conventionally thought to operate through binding to PPAR? receptors. However, it is the strong contention of the authors of this proposal that the undesirable effects of the TZDs are mediated by binding to PPAR? receptors. Moreover, it has recently been suggested that rosiglitazone, the prototypical PPAR? activator, could exert untoward acute cardiovascular effects. Contrary to the prevailing scientific view, the authors of this proposal believe that non-PPAR mediated mechanisms are responsible for the insulin sensitizing pharmacology. The co-founders of the Metabolic Solutions Development Company (MSDC) have conceived of TZDs which should display minimal or no binding to the PPAR? receptor and have applied for patent protection thereof. MSDC has commissioned the synthesis of approximately 80 analogs in this series and has extensively evaluated their activity in rodent models of Type 2 diabetes. Based on the success of demonstrating antidiabetic activity with the PPAR?-sparing TZDs in rodents, we are proposing that these analogs may also be active in a related metabolic disorder, NAFLD. In this Phase I STTR application, MSDC, in collaboration with Dr. Brian Finck of Washington University, St. Louis,, proposes to evaluate one of these analogs, MSDC-0602, for treatment efficacy in a rodent model of NAFLD. Success in demonstrating a time and dose-dependent effect of MSDC-0602 on the biochemical and pathophysiological parameters of NAFLD, will provide a solid foundation for a Phase II STTR application leading to the eventual selection of a clinical candidate for human therapeutics. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the U.S., affecting an estimated 14-24% of the population, and the incidence of this disease continues to rise concomitantly with the epidemic of obesity. There is currently no approved therapeutic treatment for this liver disease. It is the overall goal of the proposed research to identify a group of drugs from the thiazolidinedione class as candidates for treatment of NAFLD.